EP1732516A1 - Ion binding compositions - Google Patents
Ion binding compositionsInfo
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- EP1732516A1 EP1732516A1 EP05731099A EP05731099A EP1732516A1 EP 1732516 A1 EP1732516 A1 EP 1732516A1 EP 05731099 A EP05731099 A EP 05731099A EP 05731099 A EP05731099 A EP 05731099A EP 1732516 A1 EP1732516 A1 EP 1732516A1
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- pharmaceutical composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
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- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
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- A61K31/785—Polymers containing nitrogen
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- A61K31/795—Polymers containing sulfur
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/04—Acids; Metal salts or ammonium salts thereof
- C08F120/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F128/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur
- C08F128/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur by a bond to sulfur
Definitions
- Ion selective sorbents have been used in human therapy to correct disorders in electrolyte balance, in conditions such as hyperphosphatemia, hyperoxaluria, hypercalcemia, and hyperkalemia.
- Hyperphosphatemia occurs in patients with renal failure, whose kidneys no longer excrete enough phosphate ions to compensate exogenous phosphate uptake in the diet. This condition leads to high serum phosphate concentration and high calcium x phosphate product.
- high calcium x phosphate product has been held responsible for soft tissue calcification and cardiovascular disease. Cardiovascular disease is the cause of death in almost half of all dialysis patients.
- Metal-free phosphate binders such as strong base ion-exchanger materials, Dowex and Cholestyramine resins, have been suggested for use as phosphate binders. However, their low capacity of binding requires high dosage that is not well tolerated by patients.
- Amine functional polymers have been described as phosphate or oxalate binders. For example, see 5,985,938; 5,980,881; 6,180,094; 6,423,754; and PCT publication WO 95/05184. Renagel, a crosslinked polyallylamine resin, is a phosphate sequestering material introduced in the market as a metal-free phosphate binder.
- Renagel In vitro phosphate binding of Renagel is approximately 6 mmol/gm in water and 2.5 mmol/gm when measured in lOOmM sodium chloride solution.
- the recommended dosage for the targeted patient population is typically between 5 gms/day to 15 gms/day to keep the phosphate concentration below 6 mg/dL.
- Published phase I clinical trials on Renagel, performed on healthy volunteers, indicate that 15 gms of Renagel decrease the phosphate urinary excretion from a baseline of 25 mmole to 17 mmole, the difference being excreted in the feces as free and polymer-bound phosphate.
- the in vivo capacity range can be established at 0.5-1 mmol gm, which is much less than the in vitro capacity of 2.5 mmol/gr measured in saline.
- a dosage of 15 gm ofthe 2.5 mmol/gm phosphate binder would bind the entire phosphorous content ofthe average American diet, i.e. 37 mmol/day.
- the discrepancy between the in vitro binding capacity and the documented low in vivo binding capacity has a negative impact on the therapeutic benefit ofthe drug since more resin is needed to bring the serum phosphate to a safe range.
- This loss of capacity of ion-exchange resins is not limited to Renagel when used in the complex environment ofthe Gl tract environment.
- cation exchange resins in the sodium or ammonium form have been administered to patients with hyperkalemia.
- the exchange capacity of these resins were measured from isolated feces and found to be about 20% ofthe in vitro capacity (Agarwal, R., Gastroenterology, 1994, 107, 548-571).
- Renagel binder patients have noted gastrointestinal discomfort at doses as low as 1.2-2.0 gm day for an 8 week treatment period. Patients receiving 5.4 gm of Renagel/day were discontinued from treatment due to adverse events such as Gl discomfort in 8.9% ofthe cases (Slatapolsky, et al Kidney hit. 55:299-307, 1999; Chertow, et al Nephrol Dial Transplant 14:2907-2914, 1999). Thus, an improvement in in vivo binding capacity that translates to lower, better tolerated dosing would be a welcome improvement in resin- based therapies.
- the present invention provides core-shell compositions and pharmaceutical compositions thereof.
- the core-shell compositions ofthe present invention comprise of a core component and a shell component.
- the core ofthe core-shell composition is a polymer and can preferentially bind one or more target solutes, e.g., in the gastrointestinal (Gl) tract of an animal.
- the permeability ofthe shell component is modified based on the external environment.
- Another aspect ofthe invention provides methods for treatment of patients using the core-shell compositions described herein.
- the core-shell compositions are used to remove target solutes from the Gl tract.
- target solutes that can be removed from the Gl tract include, but are not limited to, phosphate, oxalate, sodium, chloride, protons, potassium, iron, calcium, ammonium, magnesium, urea, and creatinine.
- the compositions described herein are used in the treatment of hyperphosphatemia, hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, ecotopic calcification in soft tissues, hypertension, chronic heart failure, end stage renal disease, liver cirrhosis, fluid overload, sodium overload, hyperkalemia, metabolic acidosis, renal insufficiency, and anabolic metabolism.
- FIG. 1 is a schematic representation of one embodiment of a core-shell composition.
- FIG. 2 depicts the solute binding profile as a function of time for some embodiments ofthe invention.
- Figure 3 depicts the membrane preparation for determination of ion permeability.
- Figure 4 depicts the binding data of different polyethyleneimine coated beads for different cations.
- Figure 5 depicts the effect of a Eudragit RL 100 shell on magnesium and potassium binding.
- Figure 6 depicts binding of magnesium on benzylated polyethyleneimine coated
- Figure 7 depicts the stability of Ben(84)-PEI coated Dowex (K) beads under acid conditions representative ofthe acidic conditions in the stomach.
- Figure 8 depicts potassium and magnesium binding by Dowex beads coated with benzylated polyethyleneimine.
- Figure 9 depicts magnesium binding by fluoroacrylic acid beads with benzylated polyethylene imine shell.
- Figure 10 depicts a setup for determining membrane permeability.
- Figure 11 depicts the permeability of benzylated polyethyleneimine membrane.
- Figure 12 depicts the permeability and permselectivity of membranes comprising of mixtures of Eudragit RL100 and Eudragit RS 100.
- Figure 13 depicts the effects of bile acids on potassium binding by Dowex(Li) coated with polyethyleneimine.
- the present invention provides core-shell polymeric compositions. Also, methods and kits for using these compositions are described herein.
- One aspect ofthe invention is a core-shell composition
- a core-shell composition comprising a core component and a shell component.
- the core-shell composition is a polymeric composition and the core component can preferentially bind one or more target solutes, e.g., in the gastrointestinal (Gl) tract of an animal.
- Gl gastrointestinal
- the term "animal” and "animal subject” as used herein includes humans as well as other mammals.
- the core-shell composition comprises core-shell particles with a core component 2 and a shell component 4.
- the core component is capable of preferentially binding one or more target solutes and the shell component has a higher permeability for the target solutes compared to the permeability for one or more competing solutes.
- the size ofthe arrows in Fig. 1 corresponds to the magnitude ofthe permeability ofthe solutes.
- the shell ofthe core-shell composition is essentially not disintegrated during the period of residence and passage through the gastro-intestinal tract.
- target solute means a solute that is preferentially bound and/or retained by the core component ofthe core-shell composition. It is preferred that the target solute has a higher permeability across the shell compared to one or more competing solutes. In preferred embodiments, the shell preferentially allows contact of the target solute with the core.
- Target solutes include both ions and non-ionic molecules.
- the ions include both organic and inorganic ions.
- the ions also include hydrophilic ions, hydrophobic ions, hydrophilic neutral molecules, and hydrophobic neutral molecules. Examples of anionic target solutes include phosphate, chloride, bicarbonate, and oxalate ions.
- cationic target solutes include protons, sodium, potassium, magnesium, calcium, ammonium, and other heavy metal ions.
- Target solutes also include toxins such as uremic toxins.
- uremic toxins include urea, creatinine, and classes of compounds such as ribonucleosides, guanidines, polyols, peptides, purines, pyrimidines. See Nanholder et al., Kidney International, vol.63, (2003), 1934-1943.
- the target solutes excludes high molecular weight molecules like proteins, polysaccharides, and cell debris whose molecular weight are greater than about 50,000 daltons, preferably greater than 5000 daltons.
- Target solutes also include non-ionic molecules such as organic and inorganic neutral molecules, as well as hydrophilic and hydrophobic neutral molecules.
- the non-ionic molecules include biological toxins, enzymes, metabolites, drugs, bodily secretions, hormones, etc.
- the toxins bound by the compositions disclosed herein are less than about 10,000 daltons, preferably less than 5000 daltons, and even more preferably less than 2000 daltons.
- the compositions disclosed herein with suitable properties could be used to treat toxicities caused by uremia, drug overdoses or exposure to toxins such as biological toxins or chemical contaminants.
- the core-shell particle preferably binds target solutes, excluding bile acids.
- the core-shell particle preferably binds a bile acid and one additional target solute which is not a bile acid.
- the term "competing solute” as used herein means solutes that compete with the target solute for binding to a core component, but that are not desired to be contacted and/or bound to the core component.
- the competing solute for a core-shell composition depends on the binding characteristics ofthe core and/or the permeability characteristics ofthe shell component.
- a competing solute can be prevented from contacting and/or binding to a core-shell particle due to the preferential binding characteristics ofthe core component and/or the decreased permeability ofthe shell component for the competing solute from the external environment.
- the competing solute has a lower permeability from the external environment across the shell compared to that ofthe target solute.
- a competing solute is bile acids and fatty acids.
- the bile acids and fatty acids can be kept away from the core and not be allowed to bind to the core due to the permeability barrier created by the shell component that is more permeable to phosphate ions than bile acids.
- the target solute is hydrophilic ions.
- the core-shell polymeric compositions which have hydrophilic ions as target solutes are preferably used to remove hydrophilic ions from physiological fluids.
- such core-shell compositions have utility in selectively removing phosphate, oxalate and/or chloride anions.
- the hydrophilic ions removed are sodium and/or potassium ions.
- the core component ofthe core-shell particles preferentially binds at least one target solute.
- the term "preferential binding" and its grammatical equivalents are used herein to describe the favored binding ofthe target solute to the core component and/or core-shell particles compared to the binding of competing solutes.
- the preferential binding of target solute can be due to a higher binding affinity for target solutes compared to competing solutes.
- Preferential binding also encompasses an increased amount of binding of target solutes by the core component, compared to the binding of competing solutes.
- the core-shell particles bind a greater amount of target solute compared to the core by itself in the absence ofthe shell.
- the increased amount of binding can be from about 5% to 100%. It is preferred that the increase in binding of target solute in the presence ofthe shell compared to the amount bound in the absence ofthe shell is about 10% or greater, more preferred is about 25%o or greater, even more preferred is about 50% or greater, and most preferred is about 95 % or greater.
- the core-shell particles retain a significant amount ofthe bound target solute.
- the term "significant amount” as used herein is not intended to mean that the entire amount ofthe bound target solute is retained. It is preferred that at least some ofthe bound solute is retained, such that a therapeutic and/or prophylactic benefit is obtained.
- Preferred amounts of bound target solutes that are retained range from about 5% to about 100%. It is preferred that the core-shell compositions retain about 50% ofthe bound target solute, more preferred is about 75%, and even more preferred is greater than 95%. The period of retention ofthe bound sodium is preferred to be during the time that the core-shell composition is being used therapeutically and/or prophylactically.
- the retention period is preferred to be during the time of residence ofthe composition in the gastro-intestinal tract.
- the retention time is typically the period the composition is present on the topical location or the location that the local effect is desired.
- the core component is composed of polymers containing functional groups with specific binding properties for a given solute, i.e. the target solute.
- the functional groups with the desired binding properties can be incorporated in the polymer backbone or pendant to the backbone.
- the binding interactions between the target solutes and the functional groups ofthe binding core can be of various kinds including, but not limited to, acid-base, coulombic, dipolar, hydrogen bonding, covalent binding, Pj interaction, and combinations thereof.
- the preferential binding between the target solute and the competing solutes can be controlled by the rate of sorption of solutes within the core material or by the rate of permeation ofthe solutes across the shell component.
- Some ofthe characteristics ofthe shell membrane and the solutes that influence the permeation of solutes across the core-shell particles are: size and shape ofthe hydrated solute; degree of association/aggregation ofthe solute (e.g., when micelles are formed); charge ofthe solutes; hydration ratio ofthe shell; mesh size ofthe shell; and interaction between shell and solutes. [0037] Other parameters also influence the overall mass transfer of solutes to the interior ofthe core-shell particles: specific surface area (i.e. particle diameter); thickness ofthe shell; and convection current at the outside ofthe particles.
- permeability coefficient P such as the capillary pore model (Renkin equation) and the free volume model, among others.
- the polymeric composition that makes up the core and/or shell component is considered to be a homogenously hydrated network.
- the diffusion transport of solutes is considered to occur through fluctuating water-filled spaces within the polymeric network.
- the free volume diffusion model predicts that D scales with the fraction of polymer in the membrane, ⁇ , and the radius ofthe hydrated solute, r s .
- a refinement has been proposed (Peppas et al., J. Appl. Polym. Sci., 36,735- 747, 1988) as the hydrodynamic model: diffusion model
- a target solute such as phosphate ions
- a typical value of self-diffusion coefficient is IO "5 cm 2 /s.
- the permeation rate across a micron thick shell membrane is estimated to be extremely fast with respect to the time of use ofthe resin, typically hours.
- bile acid or fatty acid molecules as the competing solutes, compete for the same core binding sites as phosphate ions, their self-diffusion coefficient is inversely proportional to their size in solution, which is not so different from one of small ions. Thus, this self-diffusion coefficient may not be enough to create a permeability barrier, if the diffusion is unhindered. Accordingly, in some embodiments, several characteristics ofthe shell component are tuned so that a permeation difference is established. For example, when the mesh size ofthe shell material is in the same size range as the solute dimensions, the random walk ofthe bulkier solute through the shell component is significantly slowed down.
- the permeability ofthe solute is modulated by the degree of interaction between the solute and the shell material.
- a strong interaction can trap the solute inside the shell component, almost shutting down the migration across the shell. Examples of types of interaction include ionic, covalent, polar, hydrogen bonding, van der Waals, and hydrophobic interactions.
- the ratio between the diffusion coefficient ofthe target solute and the competing solutes through the shell is between about 1.1:1 to about 10 9 :1, preferably between about 2:1 to about 10 6 :1.
- the solute binding profile as a function of time can be schematically represented as depicted in FIG. 2.
- the target solute migrates quickly through the shell to be bound to the core material quickly attaining its binding value corresponding to a non-competing mode.
- the competing solute slowly progresses through the shell as a result of its lower permeation rate; it eventually reaches its binding equilibrium value later in time and then displaces the target solute, causing a drop in the target solute binding curve.
- the ratio of diffusion coefficients is adjusted so that, at the end ofthe time of use ofthe binder (which may correspond to mean residence time ofthe resin in the Gl) is less than about 10% to about 100% ofthe competing solutes have reached their binding equilibrium value. Preferably less than about 10%, more preferably less than about 50%, and even more preferably less than about 75% ofthe competing solutes have reached their binding equilibrium value.
- the target solutes more than about 10% to about 100% has reached its binding equilibrium value in a non-competing mode.
- the diffusion coefficient of a shell polymer can be measured by casting it as a membrane over a solid porous material, which is then contacted with a physiological solution containing the solutes of interest, and measuring steady state permeation rates of said solutes.
- Membrane characteristics can then be optimized to achieve the best cooperation in terms of selectivity and permeation rate kinetics.
- Structural characteristics ofthe membrane can be varied by modifying, for example, the polymer volume fraction (in the swollen membrane), the chemical nature ofthe polymer(s), the polymer blend composition (if more than one polymer is used), the formulation with additives such as wetting agents, plasticizers, and the manufacturing process.
- the selectivity effect provided by the shell can be obtained by measuring the binding capacity for the target solute using the core particles with and without the shell.
- SI is between about 1.05 to A 9 about 10 , even more preferably from about 1.1 to about 10 .
- the shell is a film-forming polymer.
- the shell polymer forms a crosslinked gel with a three-dimensional network structure where chains are crosslinked through covalent bonds, ionic or other bonds.
- the shell material is chemically identical to the binding core material, but the crosslink density increases outward from core to shell.
- the shell material adopts a "brush" configuration, wherein individual polymer strands are covalently attached to the core material at their termini, h this embodiment, the mesh size can be dictated by the density of chains anchored onto the surface and by the chain molecular weight.
- Permeability is also controlled by the interaction ofthe solute with the shell.
- a strong and, preferably, irreversible interaction ofthe shell with the competing solutes can trap the competing solutes within the encapsulating shell, slowing down their progression inward.
- One means of quantifying the degree of interaction between a solute and the shell is the free energy of mixing, particularly the free enthalpy of mixing, which can be predicted by solubility parameters. Solubility parameters provide a numerical method of predicting the extent of interaction between materials, particularly liquids and polymers.
- the shell material can be chosen from natural or synthetic polymers, optionally crosslinked, alone or in combination with small molecules functional additives such as wetting agents, plasticizers, permeability enhancers, solvents, moisturizing agents, pigment, and/or dyes.
- Naturally-occuring or semi-synthetic polymers include: cellulose ethers (ethyl cellulose, methyl cellulose and their copolymers), cellulose esters (cellulose acetate, cellulose propionate, cellulose phthalate, and their copolymers), hydroxypropyl cellulose, hydroxyl ethyl cellulose, chitosan, deacetylated chitosan, and the like.
- Other examples of possible shell materials are listed in the table below:
- suitable synthetic polymers that can be used in the shell component include polymers produced by free radical polymerization of ethylenic monomers (acrylic and methacrylic, styrenic, dienic, vinylic), polycondensates (polyester, polyamides, polycarbonate, polysulfone), polyisocyanate, polyurea, epoxy resins, and the like.
- Shell deposition over the core material can be carried out using coating techniques such as spraying, pan coating, fluidized bed (Wurster coating units), dipping, solvent coacervation, polyelecfrolyte inter-complex layers, and the "layer by layer” encapsulation process.
- coating techniques such as spraying, pan coating, fluidized bed (Wurster coating units), dipping, solvent coacervation, polyelecfrolyte inter-complex layers, and the "layer by layer” encapsulation process.
- Other encapsulation processes are also applicable. For example, see
- the shell can comprise several layers of distinct composition, of which one can be an enteric coating (e.g. Eudragit acrylic polymers) that disintegrates and/or solubilizes at a specific location ofthe Gl tract.
- enteric coating e.g. Eudragit acrylic polymers
- suitable enteric coatings are known in the art, for example see Remington: The Science and Practice of Pharmacy by A.R. Gennaro
- the shell can also be grown on the core component through chemical means, for example by: • chemical grafting of shell polymer to the core using living polymerization from active sites anchored onto the core polymer; • interfacial reaction, i.e., a chemical reaction located at the core particle surface, such as interfacial polycondensation; and • using block copolymers as suspending agents during the core particle synthesis.
- the interfacial reaction and use of block polymers are preferred techniques when chemical methods are used, hi the interfacial reaction pathway, typically, the periphery ofthe core particle is chemically modified by reacting small molecules or macromolecules on the core interface. For example, an amine containing ion-binding core particle is reacted with a polymer containing amine reactive groups such as epoxy, isocyanate, activated esters, halide groups to form a crosslinked shell around the core.
- the shell is first prepared using interfacial polycondensation or solvent coacervation to produce capsules. The interior ofthe capsule is then filled up with core-forming precursors to build the core within the shell capsule.
- Solvent coacervation is described in the art. For example, see Leach, K. et al., J. Microencapsulation, 1999, 16(2), 153-167. hi this process, typically two polymers, core polymer and shell polymer are dissolved in a solvent which is further emulsified as droplets in an aqueous phase. The droplet interior is typically a homogeneous binary polymer solution. The solvent is then slowly driven off by careful distillation. The polymer solution in each droplet undergoes a phase separation as the volume fraction of polymer increases. One ofthe polymer migrates to the water/droplet interface and forms a more-or less perfect core-shell particle (or double-walled microsphere).
- Solvent coacervation is one ofthe preferred methods to deposit a controlled film of shell polymer onto the core.
- the coacervation technique consists in dispersing the core beads in a continuous liquid phase containing the shell material in a soluble form.
- the coacervation process then consists of gradually changing the solvency ofthe continuous phase so that the shell material becomes increasingly insoluble.
- the change in solvency can be triggered by a variety of physical chemistry means such as , but not limited to, changes in pH, ionic strength (i.e.
- osmolality solvent composition
- solvent composition through addition of solvent or distillation
- temperature e.g when a shell polymer with a LCST ( lower critical solution temperature) is used
- pressure particularly when supercritical fluids are used.
- solvent coacervation processes when the trigger is either pH or solvent composition.
- the shell polymer is first solubilized at low pH.
- the pH is gradually increased to reach the insolubility limit and induce shell deposition; the pH change is often produced by adding a base under strong agitation.
- Another alternative is to generate a base by thermal hydrolysis of a precursor (e.g. thermal treatment of urea to generate ammonia).
- the most preferred coacervation process is when a ternary system is used comprising the shell material and a solvent/non-solvent mixture ofthe shell material.
- the core beads are dispersed in that homogeneous solution and the solvent is gradually driven off by distillation.
- the extent of shell coating can be controlled by online or off-line monitoring ofthe shell polymer concentration in the continuous phase.
- the core-shell particles are conveniently isolated by simple filtration and sieving.
- the shell thickness is typically controlled by the initial core to shell weight ratio as well as the extent of shell polymer coacervation described earlier.
- an amphiphilic block copolymer can be used as a suspending agent to form the core particle in an inverse or direct suspension particle forming process.
- the block copolymer comprises a first block soluble in the continuous oil phase and another hydrophilic block contains functional groups that can react with the core polymer.
- the block copolymer locates to the water-in-oil interface and acts as a suspending agent.
- the hydrophilic block reacts with the core material, or co- reacts with the core-forming precursors. After the particles are isolated from the oil phase, the block copolymers form a thin shell covalently attached to the core surface.
- the chemical nature and length ofthe blocks can be varied to vary the permeation characteristics ofthe shell towards solutes of interest.
- preferred shell polymers include amine functional polymers, such as those disclosed above, which are optionally alkylated with hydrophobic agents.
- Alkylation involves reaction between the nitrogen atoms ofthe polymer and the alkylating agent (usually an alkyl, alkylaryl group carrying an amine-reactive electrophile).
- the nitrogen atoms which do react with the alkylating agent(s) resist multiple alkylation to form quaternary ammonium ions such that less than 10 mol % ofthe nitrogen atoms form quaternary ammonium ions at the conclusion of alkylation.
- Preferred alkylating agents are electrophiles such as compounds bearing functional groups such as halides, epoxides, esters, anhydrides, isocyanate, or ⁇ - unsaturated carbonyls.
- RX has the formula RX where R is a CI -C20 alkyl (preferably C4 -C20), C1-C20 hydroxy-alkyl (preferably C4 -C20 hydroxyalkyl), C6 -C20 aralkyl, C1-C20 alkylammonium (preferably C4 -C20 alkyl ammonium), or CI -C20 alkylamido (preferably C4 -C20 alkyl amido) group and X includes one or more electrophilic groups.
- electrophilic group it is meant a group which is displaced or reacted by a nitrogen atom in the polymer during the alkylation reaction.
- Examples of preferred electrophilic groups, X include halide, epoxy, tosylate, and mesylate group.
- the alkylation reaction causes opening ofthe three-membered epoxy ring.
- Examples of preferred alkylating agents include a C3 -C20 alkyl halide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n- tetradecyl halide, n-octadecyl halide, and combinations thereof); a CI -C20 hydroxyalkyl halide (e.g., an 11-halo-l-undecanol); a CI -C20 aralkyl halide (e.g., a benzyl halide);
- the alkylation step on the polyamine shell precursor can be carried out in a separate reaction, prior to the application ofthe shell onto the core beads.
- the alkylation can be done once the polyamine shell precursor is deposited onto the core beads.
- the alkylation is preferably performed with an alkylating agent that includes at least two electrophilic groups X so that the alkylation also induces crosslinking within the shell layer.
- Preferred polyfunctional alkylation agents include di- halo alkane, dihalo polyethylene glycol, and epichlorohydrine.
- the level of alkylation is adjusted depending upon the nature ofthe polyamine precursor and the size ofthe alkyl groups used on alkylation. Some factors that play a role in the level of alkylation include: (a) Insolubility ofthe shell polymer under conditions ofthe Gl tract, hi particular, the low pH's prevailing in the stomach tend to solubilize alkylated polyamine polymers whose pH of ionization is 5 and above.
- the degree of alkylation is selected by an iterative approach monitoring the two variables mentioned above.
- the shell is formed with Eudragit, for example Eudragit RL 100 or RS 100 or a combination thereof, or with polyethyleneimine (PEI). These shells maybe applied by solvent coacervation technique.
- the PEI may be optionally benzylated and also optionally cross-linked. Examples of suitable cross- linkers include, but are not limited to,
- the shell thickness can be between about 0.002 micron to about 50 micron, preferably about 0.005 micron to about 20 microns.
- the shell thickness is more than about 1 micron, more preferred is more than about 10 micron, even more preferred is more than about 20 micron, and most preferred is more than about 40 micron.
- the shell thickness is less than about 50 micron, more preferred is less than about 40 micron, even more preferred is less than about 20 micron, and most preferred is less than about 10 micron.
- the shell to core weight ratio comprises between about 0.01% to about 50%, preferably between about 0.2% to about 10%.
- the size ofthe core- shell particles typically range from about 200 nm to about 2 mm, preferably being about 500 ⁇ m.
- the size ofthe core-shell particles are more than about 1 ⁇ m, more preferred is more than about 100 ⁇ m, even more preferred is more than about 200 ⁇ m, and most preferred is more than about 400 ⁇ m.
- the size ofthe core-shell particles are less than about 500 ⁇ m, more preferred is less than about 400 ⁇ m, even more preferred is less than about 200 ⁇ m, and most preferred is less than about 100 ⁇ m.
- the binding selectivity ofthe core can be assessed by standard methods.
- the core-shell particles ofthe invention are expected to have selectivity indexes SI significantly higher than those reported for known prior-art sorbent resins.
- the permeability ofthe shell changes as a function of time. In particular, the permeability ofthe shell may change over time when used in vivo.
- the resin could bind a hydrophilic ionic solute at a certain location ofthe Gl tract at a rate controlled by the solute concentration in equilibrium with the resin at that location.
- the local target solute concentration may vary as a result of dilution or solute transport across the gut membrane.
- the shell material is engineered to respond to such concentration or other physiological changes in the Gl, so that its permeability is altered; more specifically, the permeability ofthe shell maybe decreasedduring its journey through the Gl so that hydrophilic ions are no longer able to cross the shell membrane, during the later period ofthe core-shell composition's residence in the Gl tract.
- This embodiment also applies to more hydrophobic solutes such as bile acids, h the case of bile acid sequesterants, studies have shown that the poor binding rate in vivo is caused by the release of bile acids past the ileum segment ofthe gut.
- the shell component has a permeability trigger that decreases the permeability ofthe shell to bile acids, when the core-shell resin passes the ileum so that the overall capacity is conserved.
- One manner of achieving this loss of permeability to hydrophilic ions involves decreasing or even eliminating the free volume of permeation ofthe shell membrane.
- the free volume of permeation ofthe membrane can be modified by controlling the hydration rate ofthe shell, hi this manner, it is possible to almost shut down the rate of permeation by inducing a shell collapse.
- the preferred approach consists of rendering the membrane material increasingly hydrophobic so that the hydration rate decreases almost to zero.
- This can be accomplished through several ways depending upon the type of triggering mechanism.
- the triggering mechanism can be by pH change.
- the pH profile ofthe gastrointestinal tract presents several domains which may change as a function of time, but show some invariants indicated below (Fallinborg et al. Aliment. Pharm. Therap. (1989),3,605-613): TABLE 2
- Shell polymers exhibiting a chain collapse in any of these pH regions would be prone to permeability changes.
- core-shell particles suitable for binding a solute selectively in the stomach and keeping it in the particle core while the particles are moving down the small and large intestine would display high permeability to solutes at low pH and very low permeability at neutral pH.
- This can be done by having a shell polymer with hydrophobic groups and groups that ionize subject to pH change.
- polymers built from hydrophobic monomers e.g. long chain alcohol (meth)arylates, Nalkyl (meth)acrylamide
- basic monomers that ionize at low pH and remain neutral beyond their pKa
- a further drop in permeability may be desirable when pH increases (e.g. from ileum to colon) to prevent bound electrolytes being released as the resin environment changes. This can be achieved where the shell material switches from a hydrated state to a collapsed, impermeable state as the pH gets slightly basic.
- shell polymers typically contain a balanced amount of hydrophobic and acidic monomers.
- Such systems are extensively described in the literature. For example, see Kraft et al. Langmuir, 2003, 19, 910-915; Ito et al, Macromolecule, ( ⁇ 992), 25,7313-7316.
- Another means of changing shell permeability is by passive absorption. As described above, components present in the Gl tract, whether coming from the diet, produced as diet digest metabolites, from secretion, etc. are susceptible to adsorption on and within the shell in a quasi-irreversible manner and this adsorption may modify the permeability pattern by inducing membrane collapse.
- Gl tract components The vast majority of these Gl tract components is negatively charged and shows various levels of hydrophobicity. Some of these species have an amphiphilic character, such as fatty acids, bile acids, phospholipids, and biliary salts and behave as surfactants. Surfactants can adsorb non-specifically to surfaces through hydrophobic interactions, ionic interaction and combinations thereof. In the context ofthe present invention, this phenomenon can be used to change the permeability ofthe resin upon the course of binding to these surfactants during the resin's residence in the Gl tract.
- fatty acids and bile acids both form insoluble complexes when mixed with positively charged polymers.
- Kaneko et al Macromolecular Rapid Communications, 2003, 24(13), 789-7912.
- Both types of molecules present similarities with synthetic anionic surfactants, and numerous studies report the formation of insoluble complexes between anionic surfactants and cationically charged polymers. For example, see Chen, L. et al, Macromolecules (1998), 31(3), 787- 794.
- the shell material is selected from copolymers containing both hydrophobic and cationic groups, so that the shell forms a complex, preferably a tight complex, with anionically charged hydrophobs typically found in the Gl tract, such as bile acids, fatty acids, bilirubin and related compounds.
- Suitable compositions also include polymeric materials described as bile acids sequestering agents, such as those reported in US 5607669, US 6294163, US 5374422, Figuly et al, Macromolecules, 1997, 30, 6174-6184. The formation of this complex induces a shell membrane collapse which in turn lowers or shuts down the permeation rate across the said membrane.
- the shell permeability may also be modulated by enzymatic transformation, hi one embodiment the shell comprises a hydrophobic backbone with pendant hydrophilic entities that are cleaved off via an enzymatic reaction in the gut. As the enzymatic reaction proceeds, the polymer membrane becomes more and more hydrophobic, and turns from a high swollen, high permeability material to a fully collapsed low hydration membrane with minimal permeability. Hydrophilic entities can be chosen amongst natural substrates of enzymes commonly secreted in the Gl tract.
- Such entities include amino acids, peptides, carbohydrates, esters, phosphate esters, oxyphosphate monoesters, O- and S-phosphorothioates, phosphoramidates, thiophosphate, azo groups and other similar entities.
- enteric enzymes which can be used to chemically alter the shell polymer include, but are not limited to, lipases, phospholipases, carboxylesterase, glycosidases, azoreductases, phosphatases, amidases and proteases.
- the core material is chosen from polymer compositions with the desired ion binding properties.
- suitable polymers material include, but are not limited to: 1) anion binding materials such as amine functional polymers such as those described in U.S. patents 5,985,938; 5,980,881; 6,180,094; 6,423,754; and PCT publication WO 95/05184 and 2) cation exchange polymers, such as those with acid functional groups such as carboxylate, phosphonate, sulfate, sulfonate, sulfamate functional polymers and combinations thereof.
- Core-shell compositions that include anion binding materials are useful for the binding and removal from Gl tract of phosphate, chloride, bicarbonate, and oxalate ions.
- the cation exchange polymers have utility in binding and removal of physiologically important cations such as protons, sodium, potassium, magnesium, calcium, ammonium, and the like or heavy metals which cause poisoning.
- compositions that can be used in the core component include the phosphate binders in PCT publications WO 94/19379, WO 96/25440, WO 01/28527, WO 02/85378, WO 96/39156, WO 98/42355, WO 99/22743, WO 95/05184, WO 96/21454, and WO 98/17707; U.S. patents 5,698,190; 5,851,518; 5,496,545; 5,667,775; 6,083,495; and 6,509,013; and European Patent Application 01200604.5.
- Aluminum, calcium, and lanthanum salts are used as phosphate binders.
- the core-shell particle comprises of a core component comprising of a metal phosphate binder, such as aluminum carbonate, aluminum hydroxide gel, calcium carbonate, calcium acetate, and lanthanum carbonate.
- a metal phosphate binder such as aluminum carbonate, aluminum hydroxide gel, calcium carbonate, calcium acetate, and lanthanum carbonate.
- the core component has sodium ion binding properties.
- Suitable polymers that can be used in the core so as to impart the core sodium-binding properties include crown ethers. Crown ethers exhibit selectivity for certain alkali metals over others, based mainly on the hole-size ofthe crown ether size and the size ofthe metal. Crown ethers ofthe type 15-18 are preferred for use in sodium ion binding core components.
- other suitable compositions for sodium binding properties are described in co-pending patent application entitled “Methods and Compositions for Treatment of Ion Imbalances," Attorney Docket Number 29329-714.201 , filed on 30 March 2004, Application Serial Number: 10/814,527.
- the invention provides methods of preferentially binding solutes in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of core-shell compositions.
- Core shell compositions that bind hydorphillic cations and/or anions can be used to control ion homeostasis and treat electrolyte balance disorders in phosphate (hyperphosphatemia), oxalate (calcium oxalate kidney stones, oxaluria), sodium (hypertension), potassium (hyperkalemia), chloride (acidosis), or to remove toxic metals or oxidative anions in cases of poisoning.
- the core-shell compositions with anion exchange resins are particularly useful in the binding and excretion of negatively charged ions from the body.
- Core-shell compositions can also be used to bind metallic ions. These compositions can be administered orally to bind and remove from an animal various negatively charged entities and metallic species from the gastro-intestinal tract.
- the core-shell compositions ofthe present invention are used to remove phosphate, oxalate, bile acids, small molecules, proteins, metallic ions such as those comprised within the 6th and the 11th groups and 4th and 6th periods ofthe Periodic Table, also including the Lanthanoids and the Actanoids.
- the core-shell compositions with polyvicinalarnines such as those described in co-pending U.S. Patent application No. 10/701,385; entitled
- Polyamine Polymers are useful in the treatment of renal diseases, hyperphosphatemia, and the removal of bile acids, oxalates and iron from the gastrointestinal tract.
- the core-shell compositions are used in the treatment of phosphate imbalance disorders.
- phosphate imbalance disorder refers to conditions in which the level of phosphorus present in the body is abnormal.
- a phosphate imbalance disorder includes hyperphosphatemia.
- hyperphosphatemia refers to a condition in which the element phosphorus is present in the body at an elevated level.
- a patient is often diagnosed with hyperphosphatemia if the blood phosphate level is, for example, above 4.5 milligrams per deciliter of blood and/or glomerular filtration rate is reduced to, for example, more than about 20%
- Other diseases that can be treated with the methods and compositions ofthe present invention include hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, and ecotopic calcification in soft tissues including calcifications in joints, lungs, kidney, conjuctiva, and myocardial tissues.
- the present invention can be used to treat ESRD and dialysis patients.
- the core-shell compositions are used for prophylactic treatment of diseases.
- the core-shell compositions described herein can also be used to treat diseases wherein a reduction in physiological levels of salt is desired.
- the core-shell compositions can be used to remove cations such as sodium and/or anions such as chloride.
- the core-shell compositions ofthe present invention are used to treat metallic poisoning, like iron poisoning. Iron poisoning typically is a result of children inadvertently taking iron supplement tablets. In iron overdose, binding of iron to oral charcoal, bicarbonate, deferoxamine, or magnesium hydroxide are typical treatments. Gastric lavage and profuse oral fluids are used to try to flush out the iron tablets.
- Non- absorbable core-shell compositions with iron chelating properties can be used for removal of metallic iron.
- the core-shell compositions ofthe present invention also show utility in binding dietary oxalate in patients who suffer from hyperoxaluria, i.e. abnormally high levels of oxalate in the urine. Elevated urine oxalate levels are one ofthe causes of calcium-stone formation (i.e., kidney stones). Most calcium stones are composed of calcium oxalate, either alone or in combination with calcium phosphate or calcium urate.
- Elevated urinary oxalate levels can result from excessive dietary intake of oxalate (dietary oxaluria), gastrointestinal disorders that lead to malabsorption of oxalate (enteric oxaluria), or an inherited enzyme deficiency that results in excessive metabolism of oxalate (primary hyperoxaluria or PH). Dietary and enteric oxaluria can be treated with diet restriction or modifications to restrict intake of foods with high oxalate content. However patient compliance is often difficult owing to the wide distribution of oxalate and purine derivatives in many foods.
- Calcium carbonate tablets (500-650 mg/tablet; 3 tablets per meal) can also be taken to bind and remove intestinal oxalate, but again patient compliance is difficult owing to the amount of calcium carbonate needed.
- Core components made of polyvicinalamines such as those described co-pending U.S. Patent application No. 10/701,385; entitled Polyamine Polymers, Attorney Docket Number: 29329-703, filed on November 3, 2003, have high binding constants for oxalate and can be used to remove oxalate from the gastro-intestinal tract and subsequently lower the risk of kidney stone formation.
- the core-shell compositions can be co-administered with other active pharmaceutical agents depending on the condition being treated.
- This co- administration can include simultaneous administration ofthe two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
- the core-shell compositions can be co-administered with calcium salts which are used to treat hypocalcemia resulting from hyperphosphatemia.
- the calcium salt and core-shell composition can be formulated together in the same dosage form and administered simultaneously.
- the calcium salt and core-shell composition can be simultaneously administered, wherein both the agents are present in separate fonnulations.
- the calcium salt can be administered just followed by the core-shell composition, or vice versa.
- the core-shell composition and calcium salt may be administered a few minutes apart, or a few hours apart, or a few days apart.
- treating includes achieving a therapeutic benefit and/or a prophylactic benefit.
- therapeutic benefit is meant eradication, amelioration, or prevention ofthe underlying disorder being treated.
- therapeutic benefit includes eradication or amelioration ofthe underlying hype ⁇ hosphatemia.
- a therapeutic benefit is achieved with the eradication, amelioration, or prevention of one or more ofthe physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
- administration of core-shell compositions to a patient suffering from renal insufficiency and/or hype ⁇ hosphatemia provides therapeutic benefit not only when the patient's serum phosphate level is decreased, but also when an improvement is observed in the patient with respect to other disorders that accompany renal failure and/or hype ⁇ hosphatemia like ectopic calcification and renal osteodistrophy.
- the core-shell compositions may be administered to a patient at risk of developing hype ⁇ hosphatemia or to a patient reporting one or more ofthe physiological symptoms of hype ⁇ hosphatemia, even though a diagnosis of hype ⁇ hosphatemia may not have been made.
- compositions ofthe present invention include compositions wherein the core-shell compositions are present in an effective amount, i.e., in an amount effective to achieve therapeutic or prophylactic benefit.
- an effective amount i.e., in an amount effective to achieve therapeutic or prophylactic benefit.
- the actual amount effective for a particular application will depend on the patient (e.g., age, weight, etc.), the condition being treated, and the route of administration. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light ofthe disclosure herein.
- the effective amount for use in humans can be determined from animal models. For example, a dose for humans can be formulated to achieve circulating and/or gastrointestinal concentrations that have been found to be effective in animals.
- the dosages ofthe core-shell compositions in animals will depend on the disease being, treated, the route of administration, the physical characteristics ofthe patient being treated, and the composition ofthe core and shell components. Dosage levels ofthe core-shell compositions for therapeutic and/or prophylactic uses can be from about about 0.5 gm/day to about 30 gm/day. It is preferred that these polymers are administered along with meals.
- the compositions may be administered one time a day, two times a day, or three times a day. Most preferred dose is about 15 gm day or less.
- a preferred dose range is about 5 gm/day to about 20 gm/day, more preferred is about 5 gm day to about 15 gm/day, even more preferred is about 10 gm/day to about 20 gm/day, and most preferred is about 10 gm/day to about 15 gm/day.
- the amount of target solute bound and/or retained by the core-shell particles is greater than the amount if the core component is used in the absence ofthe shell.
- the dosage ofthe core component in some embodiments is lower when used in combination with a shell compared to when the core is used without the shell.
- the amount of core component present in the core-shell pharmaceutical composition is less than the amount that is administered to an animal in the absence ofthe shell component.
- the core-shell compositions used for therapeutic and/or prophylactic benefits can be administered alone or in the form of a pharmaceutical composition.
- the pharmaceutical compositions comprise ofthe core-shell compositions, one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally additional therapeutic agents.
- the compositions can be administered by injection, topically, orally, transdermally, or rectally.
- the core-shell composition or the pharmaceutical composition comprising the core-shell composition is administered orally.
- the oral form in which the core-shell composition is administered can include powder, tablet, capsule, solution, or emulsion.
- the therapeutically effective amount can be administered in a single dose or in a series of doses separated by appropriate time intervals, such as hours.
- compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing ofthe active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of admimsfration chosen. Suitable techniques for preparing pharmaceutical compositions ofthe core-shell compositions are well known in the art. [0099] In addition to the uses ofthe core-shell compositions described herein in the gastro-intestinal tract, these compositions can also be used for producing local effects in other parts ofthe body, for example in topical formulations for local effects on the skin or in systemic formulations for producing local effects in particular organs, like the liver or the heart.
- the polymers ofthe invention are provided as pharmaceutical compositions in the form of chewable tablets.
- the following types of excipients are commonly used: a sweetening agent to provide the necessary palatability, plus a binder where the former is inadequate in providing sufficient tablet hardness; a lubricant to minimize frictional effects at the die wall and facilitate tablet ejection; and, in some formulations a small amount of a disintegrant is added to facilitate mastication.
- a sweetening agent to provide the necessary palatability, plus a binder where the former is inadequate in providing sufficient tablet hardness
- a lubricant to minimize frictional effects at the die wall and facilitate tablet ejection
- a small amount of a disintegrant is added to facilitate mastication.
- sweetening agents make up the bulk ofthe inactive ingredients.
- the present invention provides chewable tablets that contain a polymer or polymers ofthe invention and one or more pharmaceutical excipients suitable for formulation of a chewable tablet.
- the polymer used in chewable tablets ofthe invention preferably has a swelling ratio while transiting the oral cavity and in the esophagus of less than about 5, preferably less than about 4, more preferably less than about 3, more preferably less than 2.5, and most preferably less than about 2.
- the tablet comprising the polymer, combined with suitable excipients provides acceptable organoleptic properties such as mouthfeel, taste, and tooth packing, and at the same time does not pose a risk to obstruct the esophagus after chewing and contact with saliva.
- the polymer(s) provide mechanical and thermal properties that are usually performed by excipients, thus decreasing the amount of such excipients required for the formulation.
- the active ingredient e.g., polymer
- the polymer comprises about 0.6 gm to about 2.0 gm ofthe total weight of the tablet, preferably about 0.8 gm to about 1.6 gm.
- the polymer comprises more than about 0.8 gm ofthe tablet, preferably more than about 1.2 gm ofthe tablet, and most preferably more than about 1.6 gm ofthe tablet.
- the polymer is produced to have appropriate strength friability and particle size to provide the same qualities for which excipients are often used, e.g., proper hardness, good mouth feel, compressibility, and the like.
- Unswelled particle size for polymers used in chewable tablets ofthe invention is less than about 80, 70, 60, 50, 40, 30, or 20 microns mean diameter, hi preferred embodiments, the unswelled particle size is less than about 80, more preferably less than about 60, and most preferably less than about 40 microns.
- Pharmaceutical excipients useful in the chewable tablets ofthe invention include a binder, such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum; a flavoring agent, such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such as magnesium stearate, stearic acid, sodium stearyl fumurate and vegetable based fatty acids; and, optionally, a disintegrant, such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, sodium starch glycolate.
- Other additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well-known in the art; see, e.g., Gennaro AR (ed), Remington's Pharmaceutical Sciences, 20th Edition.
- the invention provides a pharmaceutical composition formulated as a chewable tablet, comprising a polymer described herein and a suitable excipient.
- the invention provides a pharmaceutical composition formulated as a chewable tablet, comprising a polymer described herein, a filler, and a lubricant.
- the invention provides a pharmaceutical composition formulated as a chewable tablet, comprising a polymer described herein, a filler, and a lubricant, wherein the filler is chosen from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose, and sorbitol, and wherein the lubricant is a magnesium fatty acid salt, such as magnesium stearate.
- the tablet may be of any size and shape compatible with chewability and mouth disintegration, preferably of a cylindrical shape, with a diameter of about 10 mm to about 40 mm and a height of about 2 mm to about 10 mm, most preferably a diameter of about 22 mm and a height of about 6 mm.
- the polymer is pre-formulated with a high Tg / high melting point low molecular weight excipient such as mannitol, sorbose, sucrose in order to form a solid solution wherein the polymer and the excipient are intimately mixed.
- a high Tg / high melting point low molecular weight excipient such as mannitol, sorbose, sucrose
- Method of mixing such as extrusion, spray-drying, chill drying, lyophilization, or wet granulation are useful. Indication ofthe level of mixing is given by known physical methods such as differential scanning calorimetry or dynamic mechanical analysis.
- Methods of making chewable tablets containing pharmaceutical ingredients, including polymers are known in the art. See, e.g., European Patent Application No. EP373852A2 and U.S. Patent No.
- the polymers ofthe invention are provided as pharmaceutical compositions in the form of liquid formulations, hi some embodiments the pharmaceutical composition contains an ion-binding polymer dispersed in a suitable liquid excipient. Suitable liquid excipients are known in the art; see, e.g., Remington 's Pharmaceutical Sciences.
- spherical particles were formed by an inverse suspension procedure wherein a prepolymer (polyallylamine) is crosslinked with epichlorohydrine.
- a block copolymer was used to impart mechanical stability to the droplets during the crosslinking reaction and provide a shell membrane chemically anchored to the core particle.
- the block copolymers were prepared by RAFT living free radical polymerization method, using a dithiocarbazide compound as a reversible chain transfer agent (CTA) and a diazonitrile free radical initiator (AMVN) indicated below:
- CTA reversible chain transfer agent
- AMVN diazonitrile free radical initiator
- n-Butyl acrylate (25g, 195 mmol) and t-butyl acrylate (25g, 195 mmol) were combined with the CTA (173:1 Monomer:CTA, 616 mg, 2.26 mmol)) and AIBN (18.6 mg, 0.113 mmol).
- the monomer to CTA ratio is fixed so that the theoretical number average molecular weight (Mn) is 20,000 g.mol at 90%> conversion.
- Mn theoretical number average molecular weight
- the solution was stirred while purging with Ar for 20 minutes at room temperature. After this time, it was heated to 65°C under Ar while stirring for 3 hours and then cooled to room temperature. 1H NMR in CDC1 3 showed 87% conversion based on disappearance of monomer.
- N,N-dimethylacrylamide (10.3 ⁇ l, 0.100 mmol) and a solution of glycidyl methacrylate (5.4 ⁇ l, 0.0111 mmol, 30 wt% in DMF) were added via a robot. Every 10 minutes for the next 4 hours N,N-dimethylacrylamide (10.3 ⁇ l, 0.100 mmol) and a solution of glycidyl methacrylate (5.4 ⁇ l, 0.0111 mmol, 30 wt% in DMF) were added while the solution stirred under Ar at 55°C. After all additions had been completed, the solution was stirred for an additional 2 hours under Ar at 55°C and then cooled to room temperature.
- PAA polyallylamine
- diblock copolymer solution diblock copolymer was dissolved in toluene at 5 wt.%.
- This initial charge is agitated to 600 ⁇ m for 2 minutes and then lowered to 300 ⁇ m for 10 minutes before the first addition of epichlorohydrin. This speed is maintained through out the experiment.
- the solution was heated to 80°C and maintained at this temperature throughout the experiment.
- the beads were purified by removing the toluene, washing with 1000 ml of acetone, followed by methanol, and then a 20% solution of NaOH (to remove the surfactant), and twice more with deionized water.
- the beads were freeze dried for 3 days to give a fine white powder weighing at 160 g (92 % yield), and having a mean diameter of 93 ⁇ m.
- Diaminopropane/epichlorohydrin in the presence of surfactant (Referred to herein as: Bead-Pi-5-s)
- Example 2 The beads obtained from Example 2 are spray-coated with an ethyl cellulose polymer shell using a Wurster fluid bed coater 2"- 4"/6" Portable Unit.
- the fluidized bed unit is operated so that an average 5 microns thick coating is deposited on the core particles, using a 30wt-% solid aqueous emulsion (Aquacoat® ECD, FMC
- Results collated in this series of examples show that the core-shell particles ofthe invention display higher binding for phosphate over bare, non-encapsulated particles in simulated fluid representative ofthe real conditions of use. Some ofthe best performing core-shell materials are then assessed in binding phosphate in the ex- vivo aspirates from human intestinal content.
- Diblock is dispensed as a 5 wt-% solution in toluene
- Constant reactor composition (mg) toluene PAA H20 NaOH EPH
- Row 1 & 2 30 sec. sonication time
- Row 3 & 4 90 sec. sonication time
- Library 100517 is identical to 100516 with the exception that the beads were further treated with HCl 1 for 6hrs @60°C to deprotect the terbutylacrylate groups into acrylic acid groups.
- Polyallyamine core 2.42 1.00
- Library 100517 is identical to 100516 with the exception that the beads were further treated with HCl 1 M for 6hrs @60°C to deprotect the terbutylacrylate groups into acrylic acid groups.
- Each example comprised a library of 22 core-shell materials and one core material taken as a reference.
- the core materials are beads prepared from crosslinked 1,3-diaminopropane/epichlorohydrine as shown in Example 2 (bead 4-s, bead 3-s, and bead 5-s). They were used either as a dry powder (bead 4-s, bead 3-s) or as a slurry in toluene (bead 5-s).
- the core-shell particles were prepared in semi-continuous reactors arranged in a 4x6 library format. Each reactor had a 3 ml volume, was magnetically stirred, and temperature-controlled.
- the beads were first dispensed, followed by the addition ofthe selected solvent under magnetic agitation.
- the reaction temperature was set to 60°C.
- the shell materials were then robotically dispensed for 4 hours and the 24 reactions kept another 12 hours at the set temperature.
- the library was then cooled down to ambient temperature and the content ofthe reactors transferred to 15 ml vials.
- the core-shell beads were then washed repeatedly with a fresh volume ofthe same solvent used during the shell coupling reaction, then with isopropanol, and finally with de-ionized water. The particles were finally lyophilized. [00130]
- the chemical structures ofthe shell materials used are shown in Table 10.
- Results are shown in Tables 11-18. Results collated in this series of example show that the core-shell particles ofthe invention display higher rate of binding for phosphate over bare, non-encapsulated particles in simulated fluid representative of the real conditions of use.
- Binding capacity in a ex-vivo aspirates [00133]
- healthy patients are given a meal ofthe same composition as the one prepared for the digestion mimic and aliquots of chyme are then sampled using a tube placed in the lumen ofthe small intestine.
- Jejunal chyme is aspirated from the tube whose lumen is located at the
- Core-shell compositions bind more phosphate than the corresponding core component.
- Example 6 Method of selection of semi-permeable membrane with high potassium binding selectivity over magnesium and calcium
- This protocol describes a method to optimize polymeric materials with regards to their ion permselectivity characteristics, which then can be used as the shell component for the making of potassium selective core-shell ion-exchange particles.
- Polymeric membrane materials with different compositions were prepared by radical copolymerization of DBA (N, N' -dibutyl acrylamide) and DEAEMA (N,N'- diethylaminoethylmethacrylate) in a glove box using miniaturized reactors in a library format. AIBN was used as the initiator and ethanol as the solvent. Polymers were isolated by precipitation into water, freeze-dried, and characterized by GPC and H-NMR. The composition ofthe polymer (DBA mol%) ranges from 30% to 70% and molecular weight ranges from 200K to 300K as shown below: Table 19
- Polymer membranes were prepared by casting a 2-wt% toluene solution of
- the composite membrane was first clamped onto a glass tube with diameter of 13 mm, and then immersed into a 2 L of donor solution of cations.
- the tube was filled with 10 ml of acceptor solution (lactose solution with the same osmolality as the donor solution (240mM)).
- the acceptor solution was sampled at a specified time interval and analyzed by ion chromatography. See Figure 3.
- Donor solution was prepared by mixing the aqueous solution of NaCl,
- KCl CaCl 2 .2H 2 O
- MgSO 4 .7H 2 O The solution was buffered to pH 6 by using 14 mM of MES (2-[N-morpholine]ethanesulfonic acid] solution.
- concentrations of different cations determined by IC were as follows: [Na + ], 40.46 mM; [K + ], 31.44 mM; [Mg 2+ ], 33.25 mM; [Ca 2+ ], 22.324 mM.
- Table 14 shows the permeability coefficients of different cations at different membranes.
- polymers are more hydrophilic (Polymer D3 and D4 with DBA% 48.5 and 56.1%, respectively)
- all cations such as Na + ,K + , Mg 2+ , and Ca 2+ , are more permeable and their permeability coefficients are comparable to those through a blank dialysis membrane (RC membrane) and reflect the self-diffusivity ofthe cations.
- Beads are prepared by a direct suspension process where a mixture of 2- fluoroacrylic methyl ester/divinylbenzene/benzoyl peroxide in a weight ratio 90/9/1 are dispersed in water under high shear with polyvinylalcohol as a suspending agent. The suspension is stirred and heated at 80°C for lOhours. The residual monomer is eliminated by steam stripping. The beads are then filtered and treated with aqueous 3M NaOH to hydrolyze the polymer, then washed, treated with HCL, water- washed, and finally dried to form the desired poly ⁇ -fluoroacrylic acid particles. The average bead diameter is 250 microns as measured by Master Sizer (Malvern UK).
- Example 8 Preparation of poly-2-fluoroacrylic acid / core- (DBA-DEAEMA) / shell particles
- the core-shell particles are prepared by forming a coating of polymer D2 on the poly-2-fluoroacrylic acid beads prepared in example 5 using a Wurster coater.
- the shell polymer prepared in example 4 is first dissolved at 20 wt-% in toluene, and the thus obtained solution then dispersed in water in a 1 : 4 weight ratio with 2 wt-% based on the organic phase of CTAB (Hexadecyltrimethyl- Ammonium Bromide) as a surfactant, using a Ultra-Turrax high-shear homogeneizer.
- CTAB Hexadecyltrimethyl- Ammonium Bromide
- the toluene is then driven off by evaporation under reduced pressure.
- the average diameter ofthe dispersion particles is 0.3 micrometer, as measured by Dynamic Light Scattering.
- the poly-2-fluoroacrylic acid beads are spray-coated with the shell polymer dispersion using a Wurster fluid bed coater 2"- 4'76" Portable Unit. The fluidized bed unit is operated so that an average 5 microns thick coating is deposited on the core particles.
- Example 9 Preparation of polystyrene sulfonate/core- polyethyleneimine shell particles with Na+ and K+ selective-binding propertie Procedure for coating PEI on Dowex beads
- PEI poly(ethyleneimine), Mwl 0,000
- Dowex beads H-form, X4-
- PEI aqueous solutions with different concentrations were prepared by dissolving PEI directly into nanopure water.
- Weighed dried Dowex beads were mixed with PEI aqueous solution in library format glass tubes. After a specified reaction time, the tubes were sealed and centrifuged at 1000 rpm for 15 minutes, the supernatant solutions were then decanted off. To the beads in each tube was added nanopure water to a total volume of 10 ml and all tubes were sealed and tumbled for 30 minutes. The same tumbling-centrifuging was repeated 3 times. The beads were freeze-dried and weighted until a constant weight was obtained.
- PEI coated Dowex beads show higher Na + and K + binding than the uncoated beads (bare beads).
- the coated beads show much more selective binding than bare beads.
- the thicker the PEI coating e.g. Dowex (2.5wt-6h), coated from 2.5 wt% PEI solution for 6 hours), the more selective for the different cations.
- the binding kinetic study shows that the binding of cations equilibrates faster for the thinner coated beads and bare beads.
- Example 10 Polystyrene sulfonate beads with Eudragit shell
- Shell material Eudragit RL100 (Rohm), a copolymer of acrylic and methacrylic acid esters with 8.85-11.96% cationic ammonio methacrylate units, 10 wt% in ethanol and 10wt% triacetin.
- Core Lewatit (cross-linked polystyrene sulfonate in sodium form), size - 300 ⁇ m.
- Example 11 Polystyrene sulfonate beads with benzylated polyethylene imine shell Synthesis of benzylated polyethyleneimine (PEI) [00158] To a 250 ml of round bottom flask were charged 15.6 g of PEI (363 mmol of-NH ) and 125 ml of ethanol, this mixture was magnetically stirred until PEI was completely dissolved, then 30 g of NaHCO (FW, 84; 256 mmol) and 40 ml of benzyl chloride (363 mmol) were subsequently added. The above mixture was reacted at 55°C under nitrogen atmosphere overnight. Dichloromomethane was added to the slurry reaction mixture, followed by filtration to remove inorganic salt.
- PEI benzylated polyethyleneimine
- the shell was coated using solvent coacervation.
- the shell Ben(84)-PEI was dissolved in methanol and water mixture (3 : 1 ) at pH of 3. Shell and core were mixed for 5 minutes and methanol was removed by rotovap (40 minutes), isolated, washed, and dried.
- Binding was measured under following conditions: Donor solutions: 50 mM KCl and 50 mM MgCl 2 Bead concentration: 4 mg/ml Duration: 6 and 24 hours [00162] Results ofthe binding measurements are shown in Figure 6. Ben(84)-PEI showed selective binding for potassium after 6 and 24 hours as revealed by lower Mg 2+ binding compared to naked beads. [00163] Figure 7 depicts the stability of Ben(84)-PEI coated Dowex (K) beads under acid conditions representative ofthe acidic conditions in the stomach. The beads were exposed to pH 2 HCl for 6 hours, isolated, and dried. Binding selectivity was tested for the post-treated beads.
- Binding conditions were as follows: Donor solutions: 50 mM KCl and 50 mM MgCl 2 Bead concentration: 4 mg/ml Duration: 6 and 24 hours The coating was stable and binding selectivity was maintained at 6 and 24 hours.
- Example 12 FAA beads with benzylated polyethylene imine shell
- the shell was applied on the FAA core by the process of solvent coacervation.
- the shell, Ben(84)-PEI was dissolved in methanol and water mixture (3:1) at pH of 4.5.
- the shell and core were mixed for 5 minutes and methanol was removed by rotovap (40 minutes), isolated, washed, and dried.
- Binding was measured under following conditions: Donor solutions: 50 mM KCl and 50 mM MgCl 2 Bead concentration: 4 mg/ml Duration: 6 hours [00166] The potassium binding was calculated from actual magnesium uptake and overall binding capacity of polymer which was 5.74 meq/gm. The results are shown in
- Example 13 Coating by controlled precipitation induced by pH change
- the shell comprised of Benzylated PEI, Ben (-20%); and Ben (-40%) on a Dowex(K) core. Binding was measured in 50 mM KCl and 50 mM MgCl 2 .
- Figure 9 shows the results ofthe binding experiments. Controlled precipitation method for 40% benzylated PEI shows better coating and this combination of coating method and materials gives higher binding selectivity.
- Example 14 Membrane screening of Shell Polymers
- Shell polymers were screened by coating a flat membrane via solvent casting and using the coated membrane as the barrier in a diffusion cell, as depicted in Figure 10.
- Donor solution was 50mM 2-[N-morpholino] ethane sulfonic acid (MES) buffer at pH6.5 with 50mM K + and Mg 2+ .
- Permeability coefficient was calculated as described in Example 4 above.
- Cross-linked B-PEI was tested using this method.
- B-PEI (35mol%) was cross-linked with 1, 4-butanediol diacrylate.
- the cross-linker was reacted on the top of dried B-PEI for 4 hours.
- the screening was performed in 50 mM KCl and 50 mM MgC12 in 50 mM MES buffer.
- Cross-linker (diacrylate) reacted with B-PEI (35 mol%) membrane.
- addition ofthe cross-linker reduced permeability coefficient and also showed good selectivity.
- Binding was measured in 50 mM KCl and 50 mM of MgC12, MES buffer, pH 6.5.
- Bile acids extract used was 2 mg/ml (bile extract porcine with 60% bile acids and 40% unknowns, i.e., free fatty acids, phospholipids, etc.).
Abstract
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US10/813,872 US8282960B2 (en) | 2004-03-30 | 2004-03-30 | Ion binding compositions |
US10/814,749 US8192758B2 (en) | 2004-03-30 | 2004-03-30 | Ion binding compositions |
US10/965,274 US7488495B2 (en) | 2004-03-30 | 2004-10-13 | Ion binding polymers and uses thereof |
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